Poultry blackhead control composition and method of using same



United States Patent 2,995,490 POULTRY BLACKHEAD CONTROL COMPOSI- TIONAND METHOD OF USING SAME Ammon M. Brubaker, Sheridan, and James R.Wiley,

Myerstown, Pa., assignors to Whitmoyer Laboratories,

Inc., Myerstown, Pa., a corporation of Delaware No Drawing. Filed Sept.23, 1957, Ser. No. 685,433

Claims. (Cl. 167-534) This invention relates generally to the art ofveterinary medicine and more particularly to the chemotherapy of thedisease in poultry known as enterohepatitis, commonly called blackhead.

Blackhead disease or enterohepatitis is caused by the one celledprotozoan parasite called Histomonas meleagridis, which is too small tobe seen with the naked eye. The disease has been a serious problem forturkey raisers for many years. Losses due to the disease may be veryextenisve and in some instances have run as high as 100%, with turkeysof all ages susceptible. Young birds may suffer a very acute attack anddie without showing signs of sickness while they are still in goodflesh. Adult birds that are sick for several days before death usuallybecome very thin.

The parasite first attacks the cecal tubes, causing ulceration andthickening of the cecal tube walls. A hard yellow core which isblood-stained usually develops. At the same time these changes aretaking place in the cecal tubes, the blackhead organisms migrate to theliver where they set up sites of infection. These produce lesions on thesurface of the liver which are grayish-white or yellowish in color. As arule, the border of the lesion is raised and the center depressed. Inthe more advanced cases, these liver lesions grow together to producelarge areas of degenerated tissue. At times, the cecal tubes willulcerate, and infection spreads to the peritoneal lining producingadhesions and inflammation in the abdominal cavity. Mortality in aturkey flock usuallydevelops in 12 to 21 days after infection.

The parasite causing blackhead is passed in the droppings of infectedbirds. These parasites are readily destroyed by sunshine and air, butthey persist in the litter and on the ground for a long time whenprotected inside cecal worm eggs. Because of this it is believed thatmost birds pick up the infection by consuming infected cecal worm eggs.Even with the best management practices, blackhead is still a threat toall flocks of turkeys because they are susceptible to the disease duringthe entire growing period. Blackhead difiers from coccidiosis and otherprotozoan diseases of turkeys in that infection apparently stimulateslittle or no immunity or resistance. Thus the flock is subject torelapse after an outbreak is brought under control. Consequently, it isdesirable to provide a means of combatting this disease in turkeys whichnot only can be made effective to rid a flock after the disease has setin and become advanced, but which also may by modification, ifnecessary, be used as a preventive so that the disease will be checkedor prevented before it gets a good start.

Although blackhead has been particularly devastating in turkey flocks,the disease also attacks chickens and other poultry, but turkeys appearto be the most susceptible.

In accordance with our invention, a composition having an activechemotherapeutic effect and a method of treatment are provided forpreventing the disease of blackhead in poultry.

We have found that a certain organic compound, namely, p-ureido benzenearsonic acid, and salts thereof, may be used effectively in preventingthe disease of blackhead in poultry and that efiective dosage may beprovided by 2,995,490 patented Aug. 8, 1961 administering the compoundin a poultry ration within definite ranges of concentration which arenon-toxic.

This compound, namely, p-ureido benzene arsonic acid and salts thereofhave been found to be effective when administered by admixture,suspension or dispersion in the normal comestibles or rations ingestedby poultry. And it will be understood that these comestibles or rationsinclude the feed and drink normally partaken or consumed by the birds,such as grain, mash, scratch, and the like and water or other comestibleliquids.

The general range of concentration of the p-ureido arsonic acid ifadministered by ad libitum feeding in the ration is from 0.01% to 1.0%.If the ration is a com minuted solid, such as mash, and the acid form ofthe compound is used, the optimum concentration for effective therapy isin the range of from 0.05 to 0.1% of the weight of the feed and if usedin the drinking water effective dosage is provided at 0.02% to 0.04%which is about half the percentage concentration of the compound whenused in solid feed, such as mash.

In general, the efiective dosage when the compound is administered in anad libitum feed ration or in the drinking water will depend somewhat onthe severity of the infection and the size and age of the birds orwhether the compound is being administered only as apreventive or as atreatment for an established infection in the flock. And if administeredin the requisite concentrations to provide effective dosage, the birdsunder treatment show little or no toxic effects and turkeys inparticular which were given only preventive dosage concentrahsn of thecompound showed as good, or even better growth rate and generalthriftiness than control birds 'to which were fed the same, butunmedicated, ration.

In the case of combatting an established case of blackhead in chickens,for example, the preferred concentration of the compound for effectiveresults, if a chicken mash ration is used for administering thecompound, is a drug level or concentration of 0.1% for the first fivedays of treatment and 0.05% for the next five days. The reason for thischange in concentration during treatment is that the drug isadministered by ad libitum feeding of the medicated ration and sickbirds may not be eating normally so the concentration is doubled toprovide double the drug concentration the first five days to compensatefor. lower feed intake.

However, it will be understood that the concentration can be varied fromthe above and still obtain effective results in using the compound as apreventive in controlling blackhead in chickens, or turkeys, or otherpoultry and such concentrations may be from .01% to 1.0% of p-ureidobenzene arsonic acid in the feed ration composition, it having beenfound that most poultry can partake of a 1.0% concentration in a mashfeed without undue toxic effects. If the drug is administered indrinking water, the range of concentration for effective results iswithin the range of 0.005% to 0.05% based on the weight of the drinkingwater.

In the event that it is desired to use the medicated composition as apreventive for controlling blackhead in turkeys, as distinguished fromtreatment to stamp out a well established infection in the flock, theconcentration of the p-ureido benzene arsonic acid in the turkey feedmash which has been found to be desirable and effective is 0.0375%. Atthis drug level, namely, 0.0375% the turkeys may be fed their usualration but containing the active chemotherapeutic agent, during theentire growing period; and as a result the flock will not be set backbecause of blackhead disease for the reason that the medicated feedprevents the birds from contracting the disease. Hence, the disease willnot get a start and therefore a serious and advanced epidemic ofblackhead does not develop in the flock.

3 Although the novel features which are believed to be characteristic ofthe invention are pointed out in the annexed claims, the inventionitself and the manner in EXAMPLE A Twenty Beltsville into 5 groups of 4each at six weeks of age. The groups were designated I to V. Each groupwas fed the same commercial growing mash except that Group I containedno medication and served as a control. Groups II to V were fed the sameration as Group I except that the mash contained predeterminedpercentages of p-ureido benzene arsonic acid as set forth in thefollowing Table I. The medicated rations were started 48 hours beforeadministering embryonated cecal worm eggs to all of said five groups toinduce blackhead. The five groups were fed ad libitum. Three hundredcecal worm eggs were given to each turkey on the third, fourth and fifthday. Weight and feed consumption were recorded at the fifth, twelfth,and seventeenth days. The test was terminated at seventeen days becausethe batteries had to be vacated and fumigated for use in other scheduledtests. At the end of the seventeen days the controls were sick andshowed typical yellow droppings characteristic of blackhead but thebirds fed medicated feed thrived.

Table I The results of this test showed that the turkey poults whichreceived medicated feed containing p-ureido benzene arsonic acid atlevels of .025% to .2% did not show symptoms of blackhead disease. Itwill be understood by those familiar with this art that the term level"is commonly used to designate the concentration by weight of the drug inthe feeding medium. In post white turkey poults were divided todetermine the efiects of continuous feeding of pureido benzene arsonicacid on turkey poults and also to determine how much arsenic accumulatesin the tissues during a prolonged feed period.

One hundred and twenty-seven straight run, day old broad breasted whiteturkey poults were divided at random into four groups: thirty-one inGroup 1B; and thirty-two in each of Groups 28, 3B and 4B. These groupswere fed the levels of p-ureido benzene arsonic acid shown in thefollowing Table II continuously for 12 weeks on an all-mash basis. Thebasal ration for all groups was a well-known brand of turkey starterfeed for the first six week period and a well-known brand of turkeygrower feed for the second six week period. The basal ration did notcontain any other arsenical or coccidiostat.

Table II the feed ration Group The rearing conditions of each group werethe same: confinement on a brooder house floor using infra-red lamps asheat source.

The poults, or the experimental birds, were of poor quality on arrivaland the mortality for the first 20 days was excessive. It was determinedby diagnostic examination that the poults sufiered from a non-specificenteritis and they were treated with sulfa drugs followed by Terramycin.From the sixth to the twentieth day the poults were given this treatmentintermittently. At the end of this period the most severely infectedbirds had died and those remaining appeared to have responded to thetreatment and this medication was terminated.

The mortality record of the test is reported in Table III in two phases:The mortality for the first twenty days Table III MORTALITY TABLE (2PHASES-FIRST 2) DAYS AND 20 DAYS TO 13 WEEKS) 1st phase 2d phase TotalLot or group M 1st Percent M 20 Percent M entire Percent Treatment No.start 20 days M days to M 1 ex. M I

13 weeks 13 Control, basic 81 3 9.6 1 3. 5 4 12.9 213.. 0.0125 0P-nreido benzene arsonic acid 32 0 18.7 2 7. 6 8 25 813.. 0.025 0 obenzene arsonic acid. 82 4 12. 5 0 0 4 12. 5 0.05 P-uretdo benzenearsonic acid.... 32 0 0 1 3. 2 1 3. 2

' Totals 127 13 10 4 3. 6 17 13 ltd-mortality.

1 Calculated on birds remaining after at days.

Calculated on number of birds started. mortem examination after theseventeenth day, the four poults in the control group (Group I) showedsevere infection in the cecal tubes and two of these showed liverlesions typical of blackhead disease. The groups which received themedicated feed did not have lesions in the cecal tubes or on theirlivers, except one in Group II, which showed mild lesions in the cecaltubes. Weight gains were normal. The test shows that p-ureido benzenearsonic acid is active in suppressing blackhead disease. EXAMPLE B Aftereliminating the mortality which took place the first 20 days due to acongenital infection, it can be observed from Table III that themortality was not excessive and This example describes a test which wasconducted loss by mortality in a flock. No gross serious ill effectsEXAMPLE C In another test to determine the effectiveness of the drug,p-ureido benzene arsonic acid, for prevention of blackhead in turkeypoults, 130 straight run broad breasted white turkey poults were dividedin four groups as follows: Group 10, 32 poults; Group 20, 32 poults;Group 3C, 33 poults; and Group 4C, 33 poults. The rearing conditionswere the same for all groups, namely, confinement to a brooder housefloor, peat moss litter, and infra-red lamps as a heat source.

The basal ration consisted of a commercial turkey starter mash and aftersix weeks a commercial growing mash. These did not contain anyarsenicals, coccidiostats, or drugs for prevention of blackhead, otherthan the p-ureido benzene arsonic acid added to the feed by us asindicated in the following Table C.

The following drug levels were maintained in the feed mash which was fedad libitum and continuously for fourteen weeks on an all mash basis.Plain drinking water was, of course, available to the birds at alltimes.

Table C Drug levels, percent drug in feed mash l A blsckhead remedypurchased in the market.

In order to introduce biackhead infection, each poult was given 100embryonated cecal worm eggs at 4 weeks of age. At six weeks, embryonatedcecal worm eggs were mixed in wet mash and anequal quantity sprinkled ontop of the feeders in each pen. A post mortem examination was made oneach individual that died during the feeding period. After 14 weeks mostof the surviving birds were put on an unmedic'ated ration for 10 daysand then slaughtered.

Twelve turkeys from each of Group 2C and Group 30 (6 toms and 6 hensfrom each group) were continued on their respective medicated rationsuntil these birds were fed the medicated feed for a period of 25 weeks.A tom and a hen from each group were killed and liver and muscle tissuetaken for an arsenic assay on the last day of medication. This wasrepeated at 5, 7, and 14 days after the medicated rations werediscontinued by 7 slaughtering one torn and one hen.

A summary of the data and results of these tests are set forth in thefollowing Tables IC to VC.

SUMMARY OF DATA Turks blaekhesd test 2/23/66-6636/66 3/26] 6-tnrkeysinoculated-4 embryonated cecal eggs no observable effects) 4/ [tie-towinoculated-embryonated cecal eggs in wet mash (e1! ve) TableIC.2/23/563/2I/56 4 WEEKS OF AGE BEFORE ANY INFECTION) 5 N o. of TotalAvg. Avg. wt.

Group turkeys Died No. feed con. per Rank start rem. cons. per turkey,

turkey lbs.

Table IIC 3/21/66-4/4/66-6 WEEKS OF AGE (COVERING PERIOD OF TWOINOCULATIONS 3/26-4/2) No.0i No. Total Avg. Avg.

Group turkeys, Died rem., reed con. per wt.per Rank 8/4 3/21-4/4 4/4corfiito turkfy, ting/ray,

4/4-6/16-(6-12 WEEK PERIOD) PERIOD AFTER INOCULA- TION TO TERMINATIONAvg. Total N o. of Died, No. Feed feed Avg. Rank, teed Group turkeys,4/4-5/16 rem. co con. 1' wt. per 5/16 con.,

4/4 4/4-6/16 [)0 t, poult 2/23 to 1 Total feed consumption of nosignificance due to morbidity and mortality.

Table I VC MORTALITY REVIEW ENTIRE EXPERIMENT No. No. Percent PercentGroup st., rem., Rem., Rern., mort. Rank from Rank 2 23 3 21 4 4 5/16all black causes head no 126 12s 97 Table VC FEED CONSUMPTION REVIEW AV.PER POULT (LBS) (T.M.=25%) 1 Group 4/21 4 4/4, 6 5/16, 12

weeks weeks weeks I No significance due to morbidity and mortality.

FEED CONSUMPTION (IN POUNDS-14 DAY INTERVALS) Date Group 10 Group 20Group 30 Group 40 OBSERVATIONS AND REMARKS The control Group consumedbefore and during the period of inoculation (1st 6 weeks) as much feedas the other pens with the exception of Group 3C (.05 pureido benzenearsonic acid). See Tables IC and IIC. Nevertheless, they showed thepoorest weight gain, ranked 4th. No reason can be advanced for thislower weight unless it might be due to irregularity of sex distribution.

Group 2C (.4375% p-ureido benzene arsonic acid) showed about the sameaverage feed consumption as Groups 1C and 3C (for the first 6 weeks andranked second in weight; Tables IC and IIC. At the termination of theexperiment Group 20 had the highest average weight per poult; TableIIlC. Group 20 (.0375% p ureido benzene arsonic acid) showed a totalmortality of 21%, which was the highest of the medicated groups, butonly 16% was from blackhead after inoculation; Table IVC.

Group 30 (.05% p-ureido benzene arsonic acid) eonsumed less feed for thefirst six weeks than the other lots but had the best average weight perpoult; Tables 10 and IIC. Group 3C was tied with Group 40 in mortalityfor the entire experiment, the mortality being 9%; Table IV; but itshould be noted here that Group 3C lost one bird before inoculation soit showed only a 6% loss due to blackhead which gives it the highestprotective rating. Group 40 showed a 9% mortality for the entireexperiment all due to blackhead after inoculation so it ranks second asfar as blackhead protection is concerned to that of Group 30.

The feed consumption of Group 40 was high the first six weeks but weightgains not as good as. lots receiving p-ureido benzene arsonic acid butbetter than the control. Whether sex distribution could have influencedthis unconformity is a probability.

This series of tests show that p-ureido benzene arsonic acid isefficacious as a blackhead preventive. It appears that etfective dosagemay be provided between .0375% and .05 concentration in the feed ration.

Analyses for arsenic in muscle tissue showed a range of .05 to .11p.p.m. of arsenic (as M 0 before withdrawal of the medicated rations inGroups 2C and 3C. After two further weeks on unmedicated feed, themuscle tissue showed levels of .03 p.p.m. or less of arsenic (as As OThere was no gross dilferences noted between muscle tissue from hens ortoms or between the two Groups 2C and 3C.

Liver tissue showed a range of .67 p.p.m. As o to .33 p.p.m. beforewithdrawal of the medicated rations. After two further weeks onunmedicated rations these values ranged from .03 p.p.m. to .22 p.p.m.There were no gross diiferences between liver tissue from hens or toms.

8 EXAMPLE D A test was conducted to determine the palatability andetficacy against blackhead of the sodium salt of pareido benzene arsonicacid in the drinking water. Day-old turkey poults were received for usein this 7 test. They were grown in batteries and were not exposed TableID MEDIOATED DRINKING WATER Group I P-nnldo bsnrsno srscnle acid I None(control). 0104 Z 1 Supplied as a concentrated solution termed "W-OSoluble" which contained 5.1% p-ureido benzene arsonlo acid as thesodium salt.

AVERAGE WEIGHT (IN POUNDS) Group 26 days 33 days 40 days 47 days FEEDCONSUMPTION (1N POUNDS) Group as-ss days 3340 days 40-41 days WATERCONSUMPTION (FLUID 0Z8.) :6 to GrouB: 4 40 days 1 1, 173 2D Z 810 3D 2,M

PERCENT MORTALITY DUE TO BLAOKHEAD GrouB: P t 1 76 2D. 0 3D- 0 BLAOKHEADLESIONS Ceca! lesions Liver lesions Group N one Slight Medl- Severo NoneSlight Medl- Bevanum um 1D '10 10 2D 5 4 1 9 1 3D 4 6 10 These testsshow that the use'of p-ureido benzene arsonic acid in the drinking wateras the sodium salt prevented mortality due to blackhead disease. Thedrug was palatable in the drinking water. No ill efiects were noted.

EXAMPLE E A- test was carried out to show the efie'ct of varying levelsof p-ureido benzene arsonic acid in feed mash, fed ad libitum tochickens. A flock of leghorn cockerel chicks were divided into groups of10 each. Group 18 (control group) was fed mash, containing nomedication. Group 2E was fed the same mash but containing .0259! ofp-ureido benzene arsonic acid; Group 313 the same mash containing thesame drug at 0.05% concentration and Group 4E the same mash containingthe same drug at 0.1% concentration. All groups were fed ad libitum forthree weeks during the test which was begun at six weeks of age. Allbirds were vaccinated for fowl pox and were fed 300 embryonated cecalworms each day for three days beginning on the first day of the test.

During the course of this test there was a mortality from blackhead of50% in the control group 113. None of the birds in medicated groups(Groups 2E, 3B, 4B) died. The average rating of blackhead lesions onpost mortem examination on an arbitrary scale for no lesions to 3 forvery severe lesions was: Group 4E--rat ing .025; Group 3E--rating .2;Group 2E--rating .175 and Group 1E (controlno medication)2.275. That is,the birds which received the medication showed substantially fewerlesions and all survived, whereas the control group receiving nomedication, but the same amount of induced infection of blackhead showeda mortality of 50% during the three weeks test period and also verysevere liver and cecal lesions due to blackhead.

In addition to the laboratory tests described above, the compositionsprovided by the invention have also been used successfully as apreventive against blackhead in large commercial flocks of turkeys andchickens. In some of these, the flocks were severely exposed toblackhead, but no outbreaks occurred in any of the test birds. Themedicated feed was readily consumed and the birds grew well to -a goodfinish.

The terms and expressions which have been employed herein are used asterms of description and not of limitation, and there is no intention,in the use of such terms and expressions, of excluding any equivalentsof the features shown and described or portions thereof, but it isrecognized that various modifications are possible within the scope ofthe invention claimed.

What is claimed is:

1. A chemotherapeutic composition for use as a preventive forcontrolling blackhead in poultry which comprises a poultry feed rationand a compound selected from the group consisting of pureido benzenearsonic acid and salts thereof in the approximate concentration of 0.01%to 1.0%.

2. A veterinary chemotherapeutic composition for use as a preventive forcontrolling blackhead in poultry which comprises a combined mixture ofpoultry feed mash and p-ureido benzene arsonic acid in a concentrationof .05% to 0.1%.

3. A veterinary chemotherapeutic composition for use as a preventive forcontrolling blackhead in poultry which comprises a mixture of an aqueousdrinking liquid and p-ureido benzene arsonic acid in the form of a saltin a concentration of .005% to .05%.

4. A veterinary chemotherapeutic composition for preventing blackhead inturkeys which comprises a nontoxic combination of turkey feed mash andp-ureido benizene arsonic acid in a concentration of .02% to .05%.

5. A veterinary chemotherapeutic feed ration which may be fed ad libitumto a flock of turkeys for preventing blackhead in the turkeys whichcomprises a turkey feed mash in which is intimately intermixedapproximately .0375 of p-ureido benzene arsonic acid.

6. A veterinary chemotherapeutic composition for ad libitum feeding to aflock of poultry as a preventive for controlling blackhead in thepoultry which comprises a poultry ration and a compound incorporatedtherein selected from the group consisting of p-ureido benzene arsonicacid and salts thereof in a concentration of from 0.01% to 1.0%, saidcompound being present in amount sufiicient to provide etfective dosagewithout intolerable toxic effect upon the poultry when administered byfeeding the composition ad libitum to the poultry.

7. A process for combatting blackhead disease in a flock of poultrywhich comprises introducing into the intestinal tracts of the birds,infected with the protozoan parasite Histomonas meleagridis which causesthe disease, a poultry feed ration containing intermixed therewith from0.01% to 1.0% of a compound selected from the group consisting ofp-ureido benzene arsonic acid and salts thereof.

8. A method of preventing blackhead disease in a flock of turkeys whichcomprises introducing into the intestinal tracts of the birds infectedwith the causitive agent, namely, the protozoan parasite Histomomzsmeleagridis, by feeding ad libitum to the turkeys a turkey feed mashcontaining intermixed therewith not less than .02% and not more than .05of p-ureido benzene arsonic acid.

9. A method of preventing blackhead disease in a flock of turkeys whichcomprises introducing into the intestinal tracts of the birds infectedwith the causitive agent, namely, the protozoan parasite Histomonasmeleagridis, by feeding ad libitum to the turkeys a turkey feed mashcontaining intermixed therewith about .0375% of p-ureido benzene arsonicacid.

10. A method of preventing blackhead disease in a flock of turkeys whichcomprises introducing into the intestinal tracts of the birds infectedwith the causitive agent, namely, the protozoan parasite Histomonasmeleagridis by feeding ad libitum to the turkeys a comestible liquidration containing intermixed therewith p-ureido benzene arsonic acid ina concentration of from .005 to .05%.

References Cited in the file of this patent Hutyra: Pathology andTherapeutics of the Diseases of Domestic Animals, vol. H, 1938,Alexander Eger, Chicago, Illinois, pp. 359-361.

U.S. Dispensatory, 25th Ed., 1955, pp. 246-247.

Wantland: I. Parasitology, vol. 40, pages 479 and 480, August 1954.

Milks: Veterinary Pharmacology, Materia Medica and Therapeutics, SixthEdition, 1949, Alex Eger, Chicago, III., p. 500.

1. A CHEMOTHERAPEUTIC COMPOSITION FOR USE AS A PREVENTIVE FORCONTROLLING BLACKHEAD IN POULTRY WITH COMPRISES A POULTRY FEED RATIONAND A COMPOUND SELECTED FROM THE GROUP CONSISTING OF P-UREIDO BENZENEARSONIC ACID AND SALTS THEREOF IN THE APPROXIMATE CONCENTRATION OF 0.01%TO 1.0%.